Staphylococcus aureus-specific skin resident memory T cells protect against bacteria colonization but exacerbate atopic dermatitis-like flares in mice.

BACKGROUND: The contribution of Staphylococcus aureus to the exacerbation of atopic dermatitis (AD) is widely documented, but its role as a primary trigger of AD skin symptoms remains poorly explored. OBJECTIVES: This study sought to reappraise the main bacterial factors and underlying immune mechanisms by which S aureus triggers AD-like inflammation. METHODS: This study capitalized on a preclinical model, in which different clinical isolates were applied in the absence of any prior experimental skin injury. RESULTS: The development of S aureus-induced dermatitis depended on the nature of the S aureus strain, its viability, the concentration of the applied bacterial suspension, the production of secreted and nonsecreted factors, as well as the activation of accessory gene regulatory quorum sensing system. In addition, the rising dermatitis, which exhibited the well-documented AD cytokine signature, was significantly inhibited in inflammasome adaptor apoptosis-associated speck-like protein containing a CARD domain- and monocyte/macrophage-deficient animals, but not in T- and B-cell-deficient mice, suggesting a major role for the innate response in the induction of skin inflammation. However, bacterial exposure generated a robust adaptive immune response against S aureus, and an accumulation of S aureus-specific γδ and CD4+ tissue resident memory T cells at the site of previous dermatitis. The latter both contributed to worsen the flares of AD-like dermatitis on new bacteria exposures, but also, protected the mice from persistent bacterial colonization. CONCLUSIONS: These data highlight the induction of unique AD-like inflammation, with the generation of proinflammatory but protective tissue resident memory T cells in a context of natural exposure to pathogenic S aureus strains.

Skin-centered strategies in food allergy prevention.

While the early introduction of food allergens in the infant diet has been shown to be effective at preventing the development of food allergy (FA), its implementation in real life has been associated with various challenges. Interventions aimed at correcting skin barrier dysfunction have been explored in recent decades as a distinct or complementary mean to prevent allergic sensitization through the skin and subsequent development of FA. Studies assessing the application of emollient from birth have yielded conflicting results, and meta-analyses have demonstrated either no effect or only a slight positive effect on FA prevention. However, a careful review of the clinical trials reveals that different emollients were used, which may have explained some of the discrepancies between study results. Emollient application protocols also varied widely between studies. While firm conclusions cannot be drawn with regard to their overall efficacy at preventing FA, the available data provide valuable insight into the characteristics that could be associated with a more effective intervention. Namely, successful trials tended to use emollients with an acidic pH of 5.5, applied over the entire body, and combined with topical corticosteroids in affected areas. Consensus on the optimal strategy to restore skin barrier function could help improve the homogeneity and clinical relevance of future trials on this topic. In the meantime, clinicians should avoid products associated with worse outcomes.

Real-life experience with hazelnut oral immunotherapy.

BACKGROUND: Hazelnut oral immunotherapy (H-OIT), a promising alternative to hazelnut-free diet for patients with hazelnut allergy, has not been extensively studied. OBJECTIVE: To investigate the effectiveness of H-OIT for children with hazelnut allergy. METHODS: Retrospective medical record review of children treated by H-OIT in the University Hospital of Lyon (France) was reported. Clinical and laboratory data were collected, and the satisfaction of the children treated by H-OIT was evaluated using a questionnaire. RESULTS: A total of 70 patients treated by H-OIT for an immunoglobulin E-mediated hazelnut allergy (94.3%) or an immunoglobulin E sensitization to hazelnut (5.7%) were included. Among these, 22.9% entered the maintenance phase at 1-year consultation and 60.0% entered the maintenance phase during the study period. At home, 57.1% of the patients experienced at least 1 adverse effect and 2.9% experienced severe systemic allergic reactions. Among the 212 oral food challenges conducted at hospital, 3.3% led to severe systemic reactions and epinephrine was used 4 times. A total of 21.4% of children discontinued treatment; aversion to hazelnut was the main reason. There were 42 children aged 8 years or more and their parents who answered the questionnaire. H-OIT was considered a strain for children but effective and was recommended to other children with allergy. CONCLUSION: H-OIT seemed to be effective and well accepted by children. This is counterbalanced by a high rate of H-OIT discontinuation, mainly owing to aversion to hazelnut, and an important rate of adverse reactions, which are however mostly mild. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04841850.

Five Functional Aspects of the Epidermal Barrier.

The epidermis is a living, multilayered barrier with five functional levels, including a physical, a chemical, a microbial, a neuronal, and an immune level. Altogether, this complex organ contributes to protect the host from external aggression and to preserve its integrity. In this review, we focused on the different functional aspects.

The diagnosis of hypersensitivity to antibiotics is rarely confirmed by allergy work-up in cystic fibrosis patients.

Cystic fibrosis (CF) patients receive many antibiotic treatments for recurrent respiratory infections and frequently report antibiotic hypersensitivity reactions (HSRs). In this retrospective study, medical records of CF patients were reviewed to clarify the clinical features, the culprit antibiotics, and the prevalence of antibiotic HSRs in the CF population. From 601 CF patients, 95 suspected antibiotic HSRs occurred in 60 patients (prevalence of 10.0%). ß-Lactams were the most common inducers, but cotrimoxazole was also frequently involved. Seventy-six of 95 suspected HSRs were assessed by allergy workup including skin tests (43/76 reactions) and/or drug reintroduction as a full course of the culprit antibiotic (73 of 76 reactions). From the 43 suspected HSRs that were skin-tested, only three had positive skin tests and were not subjected to drug readministration. All the other 73 suspected HSRs received a full course of the culprit antibiotic: HSR symptoms recurred in 10 of 73 cases and therefore were considered as confirmed antibiotic HSRs; for the remaining 63 suspected HSRs that did not relapse after drug readministration, the diagnosis of antibiotic HSRs was excluded. In summary, 13 of 76 suspected HSRs were confirmed as antibiotic HSRs. The prevalence of suspected and confirmed antibiotic HSRs in CF patients appears similar to that reported in the general population. Of note, most of the antibiotic suspected HSRs are not confirmed after allergology workup. A complete allergy workup appears therefore crucial to make a correct diagnosis and to avoid unnecessary contraindication of major antibiotics.

[Management of childhood food allergies]. / Prise en charge des allergies alimentaires de l'enfant.

Food allergy reduces the quality of allergic children life because of a lethal risk. Current recommendations are favouring introduction of potentially allergenic foods according to usual, non-delayed, practices. In allergic children, intramuscular epinephrine is the key treatment of anaphylaxis. A self-injectable device must be prescribed in the presence of a severe reaction risk. Allergen avoidance is currently best to avoid an allergic reaction. Specific immunotherapy, essentially oral, is the only treatment for tolerance induction in allergic patients, and may be discussed to prevent severe reactions in the case of accidental ingestion.

L'allergie alimentaire (AA) est responsable d'une altération de la qualité de vie de l'enfant allergique, exposé à un risque parfois vital. Les recommandations pour la prévention de l'AA prévoient une introduction, puis l'administration régulière des aliments à risque selon le schéma habituel, non retardé. Chez l'enfant devenu allergique, l'adrénaline intramusculaire est le traitement de l'anaphylaxie et doit être prescrite pour une utilisation en cas de risque d'allergie sévère. Dans le quotidien, l'éviction de l'aliment en cause est la règle, avec une prévention réfléchie du risque d'allergie associée. L'immunothérapie spécifique, principalement orale, est le seul traitement ayant permis une induction de tolérance chez ces patients ; elle peut être proposée au cas par cas, notamment afin d'éviter les accidents lors d'ingestions involontaires.

Atopic Dermatitis and Self-Image Design: A Real-Life Study in Children Using Drawings.

Background: Atopic dermatitis (AD) induces alterations of external appearance and self-esteem, with impact on the personal development of the children. However, tools for estimating such suffering are lacking. We aimed to assess how children with AD represent themselves through their drawings. Methods: In this retrospective study, we included children (<18 years) suffering from AD who followed the instruction "draw yourself with and without eczema" at the end of a routine follow-up consultation. Drawings were interpreted with the child and then classified in different analysis groups by 5 independent evaluators. Results: A total of 64 children (41 [64.1%] girls and 23 [35.9%] boys, median [range] age 8 [3-7] years) made 64 drawings. Five groups of drawing were identified: "amputee" (n = 8, 12.5%), "identical" (n = 18, 28.1%), "sad" (n = 19, 29.7%), "complex" (n = 11, 17.2%), and "other" (n = 8, 12.5%). Univariate analysis found that age was differently distributed among the different drawing groups (P = 0.0047), as was the predominance of light colors (P = 0.038). The distribution of the other variables (gender, investigator global assessment score, active AD, and duration of activity) was not different among drawing groups. Conclusions: The drawing allows a majority of the AD children to express their self-image with and without eczema, as well as their feelings and their interactions with the environment and with their entourage. The visual tool proposed herein could be used during consultations, to (a) become aware of the need to treat AD, (b) better evaluate the impact of AD burden in childhood, and (c) adjust appropriately AD treatment.

Epidemiology, prevention methods, and risk factors of foot blisters in French trail ultramarathons.

BACKGROUND: Blisters are a common running injury and are known to limit runners' performance. There have been many studies on the subject with contrasting results. It would therefore be useful to describe more clearly blister epidemiology, blister prevention methods, and risk factors of blister development. METHODS: This study is a retrospective anonymous, post-race survey. Runners were contacted by email after races in France during the summer and autumn of 2021 and asked to fill-in an online survey about their experience with blisters and running experiences. RESULTS: Five hundred and thirty-three runners participated, of whom were 468 (88%) men and 47 women (12%), mean age 42±9.75. Sixty-one percent (N.=329) of runners applied blister prevention methods before the start of the race and 29% (N.=155) reported blisters at the end of the race. Most commonly used blisters prevention methods were: anti-friction cream 79% (N.=260), "anti-blister socks" 33% (N.=107), paper tape 13% (N.=44), and topical lemon application 11% (N.=36). Having a history of blisters in the past is strongly associated with blisters onset OR=15.950 (9.135-29.640; P<0.0001). Distances ran between 40 to 74 km appeared to be the less likely to cause blisters OR 0.188 (0.045-0.729; P=0.019). None of the studied blister prevention methods seemed to match the protective effect of running shorter distances. CONCLUSIONS: Having a history of previous blisters is a major risk factor for blister occurrence, while running shorter distances seems protective.

Abatacept to induce remission of peanut allergy during oral immunotherapy (ATARI): protocol for a phase 2a randomized controlled trial.

Context: While oral immunotherapy (OIT) has been shown to promote the remission of mild peanut allergy in young children, there is still an unmet need for a disease-modifying intervention for older patients and those with severe diseases. In mice models, abatacept, a cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) immunoglobulin fusion protein, has been shown to promote immune tolerance to food when used as an adjuvant to allergen immunotherapy. The goal of this study is to explore the potential efficacy of abatacept in promoting immune tolerance to food allergens during OIT in humans. Methods: In this phase 2a proof-of-concept study (NCT04872218), 14 peanut-allergic participants aged from 14 to 55 years will be randomized at a 1:1 ratio to abatacept vs. placebo for the first 24 weeks of a peanut OIT treatment (target maintenance dose of 300 mg peanut protein). The primary outcome will be the suppression of the OIT-induced surge in peanut-specific IgE/total IgE at 24 weeks, relative to the baseline. Sustained unresponsiveness will be assessed as a secondary outcome starting at 36 weeks by observing incremental periods of peanut avoidance followed by oral food challenges. Discussion: This is the first study assessing the use of abatacept as an adjuvant to allergen immunotherapy in humans. As observed in preclinical studies, the ability of abatacept to modulate the peanut-specific immune response during OIT will serve as a proxy outcome for the development of clinical tolerance, given the small sample size. The study will also test a new patient-oriented approach to sustained tolerance testing in randomized controlled trials.

Effect of nitric oxide on epithelial ion transports in noncystic fibrosis and cystic fibrosis human proximal and distal airways.

The airways of patients with cystic fibrosis (CF) exhibit decreased nitric oxide (NO) concentrations, which might affect airway function. The aim of this study was to determine the effects of NO on ion transport in human airway epithelia. Primary cultures of non-CF and CF bronchial and bronchiolar epithelial cells were exposed to the NO donor sodium nitroprusside (SNP), and bioelectric variables were measured in Ussing chambers. Amiloride was added to inhibit the Na(+) channel ENaC, and forskolin and ATP were added successively to stimulate cAMP- and Ca(2+)-dependent Cl(-) secretions, respectively. The involvement of cGMP was assessed by measuring the intracellular cGMP concentration in bronchial cells exposed to SNP and the ion transports in cultures exposed to 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one, an inhibitor of the soluble guanylate cyclase (ODQ), or to 8Z, a cocktail of 8-bromo-cGMP and zaprinast (phosphodiesterase 5 inhibitor). SNP decreased the baseline short-circuit current (I(sc)) and the changes in I(sc) induced by amiloride, forskolin, and ATP in non-CF bronchial and bronchiolar cultures. The mechanism of this inhibition was studied in bronchial cells. SNP increased the intracellular cGMP concentration ([cGMP](i)). The inhibitory effect of SNP was abolished by 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, an NO scavenger (PTIO) and ODQ and was partly mimicked by increasing [cGMP](i). In CF cultures, SNP did not significantly modify ion transport; in CF bronchial cells, 8Z had no effect; however, SNP increased the [cGMP](i). In conclusion, exogenous NO may reduce transepithelial Na(+) absorption and Cl(-) secretion in human non-CF airway epithelia through a cGMP-dependent pathway. In CF airways, the NO/cGMP pathway appears to exert no effect on transepithelial ion transport.

The role of skin dysbiosis in atopic dermatitis

The cutaneous microbiota contributes to skin barrier function, ensuring effective protection against pathogens and contributing to the maintenance of epidermal integrity. Dysbiosis is frequently present in atopic dermatitis (AD), a chronic inflammatory disease associated with skin barrier defects. Dysbiosis is associated with reduced bacterial diversity and marked Staphylococcus aureus colonization, which is favoured in the case of certain local AD-specific properties such as reduced skin acidity, eased bacterial adhesion and decreased antimicrobial peptide production. Furthermore, S. aureus-associated skin dysbiosis, via the production of staphylococcal virulence factors, may also participate in the immunopathology of AD by altering the epidermal barrier and inducing an inflammatory response. However, there are currently no arguments for recommending screening for, and treatment of S. aureus-associated dysbiosis outside the setting of cutaneous superinfection. Nonetheless, modulation of the skin microbiota may hold promise for AD management. Here, we describe the relationships that exist between the skin microbiota and AD.

Viral Infections and Cutaneous Drug-Related Eruptions.

In the general population, up to 10% of children treated by antibiotics have cutaneous adverse drug reaction, but allergy is confirmed in less than 20% of patients. Most of the non-allergic reactions are probably due to virus, such as enterovirus acute infection or Ebstein-Barr Virus (EBV) acute infection or reactivation. Especially in children, viruses have the propensity to induce skin lesions (maculopapular rash, urticaria) due to their skin infiltration or immunologic response. In drug-related skin eruptions, a virus can participate by activating an immune predisposition. The culprit antibiotic is then the trigger for reacting. Even in severe drug-induced reactions, such as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome, viruses take part in immune phenomena, especially herpes viruses. Understanding the mechanisms of both virus- and drug-induced skin reaction is important to develop our clinical reflection and give an adaptive care to the patient. Our aim is to review current knowledge on the different aspects and potential roles of viruses in the different type of drug hypersensitivity reactions (DHR). Although major advances have been made those past year, further studies are needed for a better understanding of the link between viruses and DHR, to improve management of those patients.

Detection of skin alterations in mild-to-moderate chronic venous disease using non-invasive techniques.

BACKGROUND: Chronic venous disease (CVD) is secondary to venous hypertension, leading to vascular inflammation and tissue changes. The impact of CVD on skin structure and barrier function is not well characterized. OBJECTIVE: We aimed to assess the characteristics of skin alterations in mild-to-moderate CVD by non-invasive techniques based on a prospective exploratory study. MATERIAL & METHODS: Female subjects (30-75 years) with CVD (Stage C2 to C4, CEAP classification) were eligible. Stage C0-C1 CVD subjects were used as controls. Women with leg surgery or a medical history that could impact the results were excluded. The skin changes on lesional (LS) and non-lesional (NLS) areas were assessed by biometric analysis including skin echography, viscoelasticity evaluation, confocal microscopy and trans epidermal water loss (TEWL) measurements. RESULTS: Thirty-four subjects were enrolled. Based on computation of 26 biometric parameters using Principal Component Analysis, a significant difference between LS and NLS zones, regardless of the CEAP class, was evidenced. C2-C4 subjects presented with dermal thickening suggesting oedema associated with decreased cell density, while no difference in skin viscoelasticity was observed compared to the C0-C1 control group. Epidermal structural modifications were associated with increased TEWL correlating with CVD severity. CONCLUSION: Skin alterations in CVD patients are detectable by non-invasive methods. These findings may help to better assess new therapeutic strategies.